Anti-spasmodics specific for peptic ulcer



aga v55 AN'ir-sPAsMobIcs SPECIFIC FoR PE'PTIC ULCER Iolin H. Biel, Milwaukee, Wis., assignor to Lakeside Lahoratories, Inc., a corporation of Wisconsin No Drawing. Application April 8, 1957 Serial No. 651,165

13 Claims. (Cl. 167-65) This invention relates to an ester of cyclic aminoalcohols and particularly to the benzilic acid ester of N- ethyl-3-hydroxypiperidine, non-toxic onium derivatives thereof, and pharmaceutical compositions of the same.

This application is a continuation-in-part of application Serial No. 217,413, filed March 24, 1951, which is a continuation-in-part of application Serial No. 180,295, filed August 18, 1950, now abandoned.

The reduction of smooth muscle spasm, whether of musculotropic or neurotropic origin, by atropine and by various synthetic compounds related in structure to atropine or papaverine, is well known. While many of those compounds will effectively abolish one or the other type of spasm, they are not capable of relieving both types of muscle spasm. Furthermore, the action of the known compounds is usually accompanied by undesirable side effects such as dilation of the pupil of the eye, dryness of the mouth, large increase in rate of heart beat, hypertension, nausea and vomiting.

Some esters of N-alkyl-4-piperidinol have been found to be active anti-spasmodics or spasmolytics, but such esters have never been put into use. It is well known that changes in the positions of certain substituents on the piperidine ring may produce profound dififerences in the physiological activity and effects of such compounds, which differences are not predictable. Thus, N-methyl-4- phenyl-4-propionoxypiperidine is a potent analgesic whereas the corresponding N-methyl-2-phenyl-2-propionoxypiperidine has only slight analgesic properties and beta-4- methyl-piperidine-ethyl benzoate has considerable anesthetic action while the 2- and 3-methyl derivatives have no such action. Hence, it will be seen that shifting a group from the 4-position of the cause complete loss of activity.

is, therefore, an object of the present invention to provide a compound for pharmaceutical purposes and having the effect of reducing either involuntary'muscle or nervous spasm.

Another object of the invention is to, provide a compound having an anti-spasmodic effect-inhumans, which compound is long/lasting] in action and which will have only a few undesirable side reactions ofminor importance.

A further object of the invention is to provide a series of substituted acetic acid esters of N-lower alkyl-3-piperidinol, inwhich the lower alkyl has at least two carbons, having longer activity and side reactions both less in numher and of lower intensity than other compounds now in usefonreducing spasm of human muscle or nerves.

l have fou nd that N-lower alkyl-Q-piperidyl benzilate,

piperidine ring may Patented Dec. 22, 1959 2 in which the lower alkyl has at least two carbons, of the formula -oooo t@ N in which R represents a lower alkyl of at least two carbons, in the form of non-toxic onium salts are efiective antispasmodics in both musculotropic and neurotropic spasms and have long duration of action with fewer undesirable side eifects than various other anti-spasmodics now used.

Surprisingly, N-ethyl-3-piperidyl benzilate onium salts have a pronounced and selective action in the stomach, and have been found to be especially effective in the treatment of peptic ulcer, without significantly altering normal tonus or motility of the stomach or intestines. These results are achieved, furthermore, with only infrequent urinary diificulty, constipation], mydriasis and dryness of the mouth. Gastric hypermotility is curbed and gastric secretion and total acid are reduced greatly. Unlike other anti-spasmodics, no tolerance or loss of chicacy to N-ethy1-3-piperidyl benzilate onium salts has been found after long periods of administration.

Such unexpected specific activity in the stomach is even more surprising because the next adjacent homolog N- methyl-3-piperidyl benzilate, as the methyl bromide, does not have this specific activity but, instead, is specific for treating spasm of the colon. 1

The N-lower alkyl-3-piperidyl benzilate may be prepared by mixing an N-lower alkyl-3-chloro-piperidine and benzilic acid in isopropanol and refluxing the mixture. After filtering and concentrating the reaction mixture in vacuo, it is added to water, acidified and the unreacted acid removed with ether. After neutralizing the aqueous layer, the product is extracted with ether and the solution dried. After removing the ether, the free base is obtained by vacuum distillation.

The onium salts of N-lower alkyl-3-piperidyl benzilate, said lower alkyl having at least two carbons, are readily formed by contacting the free base with a lower alkylating agent in the presence of a suitable solvent such as anhydrous ether. The desired salt forms quickly and generally precipitates from solution. Lower alkylating agents such as methyl bromide, methyl chloride, methyl iodide,

. the corresponding ethyl halides, and dimethyl sulfate and diethyl sulfate are representative reactants that may be used to form the desired onium salts. Such onium salts may be conveniently represented by the formula R. is a lower alkyl of at least two carbons, and Y is a non-'. toxic anion, particularly the bromide, chloride," iodide and: i: f te n n a .t a

Such N-ethyl-3-piperidyl benzilate onium salts may also be formed by contacting N-methyl-3-piperidyl benzilate as the free base with an ethylating agent, such as ethyl bromide, because it makes no difference whether the N-ethyl group is initially present on the tertiary base or is added when an onium salt is formed.

The following examples illustrate the preparation of the free base and a representative onium salt thereof:

EXAMPLE 1 N-ethyl-3-piperidyl benzilate N-ethyl-3-chloropiperidine was prepared according to the method of Fuson and Zirkle described in volume 70, I. Am. Chem. Soc., page 2760.

12.0 grams (0.081 mole) of N-ethyl-3-chloropiperidine was mixed with 18.6 g. (0.081 mole) of benzilic acid and 80 cc. of anhydrous isopropyl alcohol as a solvent. The mixture was refluxed for seventy-two hours. The solution was then filtered and concentrated at 30 mm. of mercury. The concentrate was dissolved in water, acidified with hydrochloric acid and extracted with etherto' remove the unreacted benzilic acid.

The aqueous layer was neutralized with sodium-bicarbonate and the product was extracted with ether., The ethereal solution of the product was dried with potassium carbonate, the ether was removedby distillation'and'the I residue was 'distilled' at 0.12-0.18 mm; of mercury, the

boiling'point being l94198 C. A yieldof 16.5 g.- (60% of'theoretical) of N-ethyl-3-piperidyl-benzilate was obrained? EXAMPLETZ N 'ethylai-piperidyl benzilate' methobi'omide- O-(Lds N4 Br 34 grams (0.1mole) ofthe basic ester, prepared asin Example 1, is dissolved in 75 cc. of isopropyl alcohol-and treated with 9.5 g. (0.1 mole) of methyl bromide. The mixture is" allowed to stand at room temperature until precipitation is complete. The product is removed by filtration and washed with .isopropyl alcohol, yield 33 g.,

M.P. 175177 C. On recrystallization from isopropyl alcohol, the M.P. was raised to 179-180'C. dec.

Analysis.'-Calcd.'for 0211 3010,; Br, 18.45; N, 3.23. Found: Br, 18.30; N, 3.23.

The N-ethyl-3-piperidyl benzilate onium salts-are highly:

activecompoundsorally. The recommended dosage-is 5 mg. taken four times a day, i.e., before each meal and before bedtime. However, lower doses such as 2.5 mg;

give useful resultsand higherdoses such as mgm. may

be administered without adverse side effects.

Pharmaceutical; formulations are usually preparedof a predetermined amount of'an N-ethyl-3-piperidyl benzilate' onium salt and made into tablets, capsules, powders and solutions as desired. Carriers such as starch, sugar,

talcandwater may be used insuch formulations. Binders, such as gelatin. andlubricants such as sodium stearate:

ins-significant. dryness of 'the mouth and dilation. of-tthe eye pupil, comprising a member of the group consisting 4 of N-lower alkyl-3-piperidyl benzilate, said lower alkyl having auleast two carbons, and compounds ofthe formula wherein R is a lower alkyl group, R is a lower alkyl of at least two carbons, and Y is a non-toxic anion, and a pharmaceutical carrier.

2.. A pharmaceutical composition in unit dosage form;v adapted for human antispasmodic treatment without causingssignificant dryness ,of the mouth and dilation 50f th'e e eye pupil, comprising a compound 'ofthe formula wherein-:Riis ailower alkyl group, R is.a lower alkyl of -at;- -1 least two carbons,wand'Y is anon-toxic anion,. andzaw.

pharmaceutical carrier.

3.:= A pharmaceutical composition .in unit. dosage .form; adapted fo'r human antispasmodic treatment without.caus'-.1-

ing significant dryness of the mouth and dilation ofxthe: eye pupil, comprising N-ethyl-3-piperidyl benzilate methobromide and .a' pharmaceutical carrier.

4. Apharmaceutical compositionv in unit dosage form;- adapted .forhuman antispasmodic treatment without cause.

ing significant dryness of the mouth and dilation...of"the=- eye-pupil, comprising an N-ethyl-3-piperidyl benzilateloweralkyl halide inwhich the halide is a halogen other than .fluorine, and a pharmaceutical carrier.

5. The processwhich comprises administeringa com-p pound toa humanfor its therapeutic antispasmodicetfecti without causing significant dryness of the mouth and dila-,- tion of the eye pupil, said compound being of theformula wherein R is a lower .alkyl group, R' is-a lower alkylofz. at least two carbons, and Y is a non-toxic. anion,.

6. The process which comprises administering N-ethyl:

3-piperidyl benzilate methyl bromide to ;a human forits...

therapeutic. antispasmodic .efiect without causing significant dryness of the mouth and. dilation of ,the eye pupil...

7. A member of the group consisting of N-lower alkylr 3-piperidyl benzilate, said lower alkyl having aleastttwo carbons, andfcompounds of the formula wherein'Y. is a nontoxic anion, R is a lower alkyl group and R is a loweralkyl of at least two carbons.

8. N-ethyl-3' piperidyl benzilate.

9. N-ethyl 3-piperidyl benzilate lower alkyl halide;

where the-lower ;a.lkyL- halide is' a member selected from 9,918,406 5 the group consisting of lower alkyl bromide, lower alkyl chloride: and a lkyl iodld? Grant: Hackhs Chem. Dictionary, 3rd ed., 1944, p.

10. N-ethyl-3-p1pendyl benzllate methyl halide where 594, McGraw Hi11 the methyl halide is a member selected from the group Bummer et at L Am. c Soc" VOL 65, 1943, consisting of methyl bromide, methyl chloride, and methyl 5 262451 lodlde- Blicke et al.: J. Am. Chem. Soc., vol. 64, 1942, pp. 428- 11. N-ethy1-3-p1per1dyl benzllate methyl chlorlde. 431 12. N-ethyl;-3-piperidyl benzilate methyl bromide. 13. N-ethyl-3-piperidyl benzilate methyl sulfate.

OTHER REFERENCES McElvain et al.: J.A.C.S., vol. 70, January 1948, pp.

1826-28. 10 Ford-Moore et al.: J. Chem. Soc. (London), 1947, pp. References Cited in the file of this patent 55-60.

UNITED STATES PATENTS COU.S. D1sp., 25th ed., 1955, pp. 1788-1790, Llpplncott 2,127,547 Wolfes et a1 Aug. 23, 1938 Sollman: A Manual of Pharmacology, 7th ed., 1948, 2,533,002 Feldkamp Dec. 5, 1950 15 p. 46, left 001., W. B. Saunders Co. 

1. A PHARMECEUTICAL COMPOSITION IN UNIT DOSAGE FORM ADAPTED FOR HUMAN ANTISPASMODIC TREATMENT WITHOUT CAUSING SIGNIFICANT DRYNESS OF THE MOUNT AND DILATION OF THE EYE PUPIL, COMPRISING A MEMBER OF THE GROUP CONSISTING OF N-LOWER ALKYL-3-PIPERIDYL BENZILATE, SAID LOWER ALKYL HAVING AT LEAST TWO CARBONS, AND COMPOUNDS OF THE FORMULA 